Combined QM/MM and path integral simulations of kinetic isotope effects in the proton transfer reaction between nitroethane and acetate ion in water

Gao, Jiali; Wong, Kin Yiu; Major, Dan Thomas

doi:10.1002/jcc.20810

Cited by 45 publications

(66 citation statements)

References 63 publications

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“…However, the secondary KIEs are smaller in NAO than in water. Interestingly, the product of the primary and secondary deuterium KIEs in water yields a value of 8.9, somewhat greater than the computed value of 8.3 for the perdeuterated substrate (7,31), suggesting that there is slight deviation from the rule of geometric mean. For the enzymatic reaction, the rule of geometric mean is followed.…”

Section: Crystal Structure and Computational Model Of The Michaelis Cmentioning

confidence: 64%

“…Consequently, the quality of such a specific reaction model (22,31) is comparable with ab initio calculations at the G3 level. The calibration was done only for the reaction in the gas phase, i.e., the intrinsic performance of the QM model, and the performance of the QM/MM potential was validated for the solution phase reaction (31).…”

Section: Methodsmentioning

confidence: 80%

“…To evaluate the KIEs, the centroid path-integral simulations were carried out for the light isotopic reactions, and the ratio of the partition function between two isotopic reactions was determined by free-energy perturbation theory from the light mass into a heavier one (25). A unique feature of our PI-FEP/UM method is that highly accurate KIEs, including secondary KIEs, can be obtained because a single set of simulations is performed (23,31). In contrast, two separated simulations are needed in other approaches to obtain the quantum mechanical PMFs, one for each isotopic reaction, and the statistical fluctuations in the computed free energy barriers are typically larger than the free energy difference, especially for secondary KIEs.…”

Section: Methodsmentioning

confidence: 99%

“…In PI-FEP/UM, the ratio of the quantum partition functions for different isotopes, which yields the KIEs, is obtained by free-energy perturbation from a light isotope mass into a heavier one within the same centroid path-integral simulation (23), avoiding the difference between two free-energy barriers with greater fluctuations than the difference itself for the two isotopic reactions. Consequently, the PI-FEP/UM method is unique in that it yields accurate results on computed KIEs, including secondary KIEs that are not possible by other pathintegral simulation methods (23,31). The method has been demonstrated in a series of studies of chemical reactions in solution and in enzymes (22,31,32).…”

mentioning

confidence: 99%

“…Consequently, the PI-FEP/UM method is unique in that it yields accurate results on computed KIEs, including secondary KIEs that are not possible by other pathintegral simulation methods (23,31). The method has been demonstrated in a series of studies of chemical reactions in solution and in enzymes (22,31,32).…”

mentioning

confidence: 99%

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Differential quantum tunneling contributions in nitroalkane oxidase catalyzed and the uncatalyzed proton transfer reaction

Major

Héroux

Orville

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The proton transfer reaction between the substrate nitroethane and Asp-402 catalyzed by nitroalkane oxidase and the uncatalyzed process in water have been investigated using a path-integral free-energy perturbation method. Although the dominating effect in rate acceleration by the enzyme is the lowering of the quasiclassical free energy barrier, nuclear quantum effects also contribute to catalysis in nitroalkane oxidase. In particular, the overall nuclear quantum effects have greater contributions to lowering the classical barrier in the enzyme, and there is a larger difference in quantum effects between proton and deuteron transfer for the enzymatic reaction than that in water. Both experiment and computation show that primary KIEs are enhanced in the enzyme, and the computed Swain-Schaad exponent for the enzymatic reaction is exacerbated relative to that in the absence of the enzyme. In addition, the computed tunneling transmission coefficient is approximately three times greater for the enzyme reaction than the uncatalyzed reaction, and the origin of the difference may be attributed to a narrowing effect in the effective potentials for tunneling in the enzyme than that in aqueous solution.PI-FEP/UM simulations ͉ enzyme catalysis ͉ kinetic isotope effects ͉ X-ray structure A lthough the dominant factor in enzyme catalysis is the lowering of the quasiclassical free energy barrier of the enzymatic reaction in comparison with the uncatalyzed process (1-3), quantum mechanical tunneling has been recognized to also play a role in enzymatic hydrogen transfer reactions (2, 3). An intriguing, yet unanswered, question is whether enzymes have evolved to enhance tunneling to accelerate the reaction rate because quantum effects on rate acceleration are much smaller than hydrogen bonding and electrostatic stabilization of the transition state (1, 4, 5). Nevertheless, a small factor of two in rate enhancement can have important physiological impacts. Although it appears straightforward to address this question by comparing the enzymatic and the uncatalyzed reaction in solution, the difficulty is to design a model system that mimics exactly the same enzymatic reaction and mechanism. The present study examines the structure of nitroalkane oxidase (NAO) complex with nitroethane and kinetic isotope effects at the primary and secondary sites for the enzymatic and the uncatalyzed reaction. The computational findings are consistent with experimental data, suggesting that there is a differential tunneling effect for the proton transfer reaction in NAO and in water. Analysis of tunneling paths reveals that the enzyme reduces both the free energy of activation and the width of the effective potential, resulting in enhanced proton tunneling in the active site.The flavoenzyme NAO catalyzes the conversion of nitroalkanes to nitrite and aldehydes or ketones (Fig. S1) (6). The ␣-proton abstraction of the small substrate nitroethane by Asp-402 is rate-limiting, which is accelerated by a factor of 10 9 over the uncatalyzed reaction between n...

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Section: Crystal Structure and Computational Model Of The Michaelis Cmentioning

confidence: 64%

Section: Methodsmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Differential quantum tunneling contributions in nitroalkane oxidase catalyzed and the uncatalyzed proton transfer reaction

Major

Héroux

Orville

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Biomolekulare Simulationen mit mehreren Auflösungsniveaus: ein Überblick über methodische Aspekte

Meier¹,

Choutko²,

Dolenc³

et al. 2013

Angewandte Chemie

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Theoretische und computergestützte Modellierungen, die der Erklärung experimenteller Beobachtungen im Hinblick auf ein bestimmtes chemisches Phänomen oder einen bestimmten chemischen Prozess dienen, erfordern eine Reihe von Annahmen. Diese Annahmen betreffen die essentiellen Freiheitsgrade, die Art der Wechselwirkungen und die Erzeugung eines Boltzmann‐Ensembles oder einer Konfigurationstrajektorie. Abhängig von den Freiheitsgraden, die für den interessierenden Prozess unabdingbar sind, wie z. B. elektronische, nukleare oder atomare, molekulare oder supramolekulare, müssen quantenmechanische oder klassisch‐mechanische Bewegungsgleichungen angewendet werden. In Simulationen mit unterschiedlichen Auflösungsniveaus werden verschiedene Ebenen wie elektronische, atomare, supraatomare oder supramolekulare Ebenen in einem einzigen Modell vereint. Dies erlaubt eine Steigerung der Recheneffizienz, wobei eine ausreichende Genauigkeit im Hinblick auf die bestimmten Freiheitsgrade erhalten bleibt. Im Folgenden wird ein Überblick über die grundlegenden Herausforderungen und Annahmen in Bezug auf Modellierungen mit unterschiedlichen Auflösungsniveaus gegeben. Zur Veranschaulichung werden die unterschiedlichen katalytischen Eigenschaften zweier Enzyme, die sich in ihrer Struktur ähneln, jedoch unterschiedliche Substrate binden, im Hinblick auf diese Substrate unter Verwendung von Simulationen mit elektronischen, atomaren und supramolekularen Auflösungsniveaus untersucht.

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Multi‐Resolution Simulation of Biomolecular Systems: A Review of Methodological Issues

Meier¹,

Choutko²,

Dolenc³

et al. 2013

Angew Chem Int Ed

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Theoretical-computational modeling with an eye to explaining experimental observations in regard to a particular chemical phenomenon or process requires choices concerning essential degrees of freedom and types of interactions and the generation of a Boltzmann ensemble or trajectories of configurations. Depending on the degrees of freedom that are essential to the process of interest, for example, electronic or nuclear versus atomic, molecular or supra-molecular, quantum- or classical-mechanical equations of motion are to be used. In multi-resolution simulation, various levels of resolution, for example, electronic, atomic, supra-atomic or supra-molecular, are combined in one model. This allows an enhancement of the computational efficiency, while maintaining sufficient detail with respect to particular degrees of freedom. The basic challenges and choices with respect to multi-resolution modeling are reviewed and as an illustration the differential catalytic properties of two enzymes with similar folds but different substrates with respect to these substrates are explored using multi-resolution simulation at the electronic, atomic and supra-molecular levels of resolution.

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Combined QM/MM and path integral simulations of kinetic isotope effects in the proton transfer reaction between nitroethane and acetate ion in water

Cited by 45 publications

References 63 publications

Differential quantum tunneling contributions in nitroalkane oxidase catalyzed and the uncatalyzed proton transfer reaction

Differential quantum tunneling contributions in nitroalkane oxidase catalyzed and the uncatalyzed proton transfer reaction

Biomolekulare Simulationen mit mehreren Auflösungsniveaus: ein Überblick über methodische Aspekte

Multi‐Resolution Simulation of Biomolecular Systems: A Review of Methodological Issues

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